The Fat1 cadherin and vascular remodeling Abstract: Understanding of the factors that govern vascular remodeling, a process central to the pathogenesis of clinically important vascular diseases such as atherosclerosis, restenosis, saphenous vein graft occlusion, and transplant arteriosclerosis, is incomplete. We recently found that the protocadherin Fat1 is expressed by vascular smooth muscle cells (VSMC) in multiple models of vascular disease, and our work, together with reports from others, lead us to hypothesize that Fat1 has important effects on vascular remodeling. Human Fat1, an extremely large cell surface protein, consists of a 4178 aa extracellular domain, a single 24 aa transmembrane region, and a 387 aa intracellular domain. Studies by investigators working in non-vascular systems have shown that Fat proteins are involved in regulation of cytoskeletal remodeling and cellular proliferation, migration, and polarization. Recent findings indicate that the Fat1 intracellular domain can interact with Ena/VASP proteins, which are known to be involved in regulation of cytoskeletal dynamics, cell migration and proliferation. Our published studies indicate that Fat1 expression is upregulated by growth factors and cytokines important in vascular remodeling, including angiotensin II, bFGF, and PDGF-BB. Despite this observation, overexpression of the intracellular domain of Fat1 reduces growth of VSMCs, which suggests that Fat1 negatively regulates VSMCs during vascular remodeling. Moreover, inhibition of Fat1 expression significantly potentiates cell growth while limiting migration, indicating that Fat1 integrates VSMC growth and migration activity in limiting the former while facilitating the latter. Our work shows also that Fat1 is processed by cleavage, that the Fat1 intracellular domain accumulates in the cell nucleus, and that it associates with robust transcriptional activity. To further our understanding of the role of Fat1 in VSMC biology and vascular remodeling, we propose to define how both intracellular and extracellular Fat1 mediate changes in VSMC activity, and to determine the importance of Fat1 in vascular remodeling in vivo. Because Fat1 expression is induced in vascular remodeling, and because it has substantial effects on VSMC growth and migration, better understanding of its molecular functions may lead to novel therapeutic approaches for vascular diseases. PUBLIC HEALTH RELEVANCE: Vascular diseases that cause myocardial infarction, stroke, and poor circulation remain the greatest cause of death, disability, and health care expense in our society. Our work addresses novel molecular mechanisms that may govern the changes in arterial cells and artery wall structure that eventually result in vascular obstruction and disease. These studies in cell culture and relevant mouse models may lead to new approaches for prevention and treatment.